The critical role of α1-glycine receptor (α1-GLYRs) in pathological conditions such as epilepsy is well known. In the present study, structure-activity relations for a series of phenylalanine derivatives carrying selected hydrogen bond acceptors were investigated on the functional properties of human α1-GLYR expressed in Xenopus oocytes. The results indicate that one particular substitution position appeared to be of special importance for control of ligand activity. Among tested ligands (1-8), the biphenyl derivative (2) provided the most promising antagonistic effect on α1-GLYRs, while its phenylbenzyl analogue (5) exhibited the highest potentiation effect. Moreover, ligand 5 with most promising potentiating effect showed in-vivo moderate protection when tested in strychnine (STR)-induced seizure model in male adult rats, whereas ligand 2 with highest antagonistic effect failed to provide appreciable anti(pro)convulsant effect. Furthermore, ligands 2 and 5 with the most promising effects on human α1-GLYRs were examined for their toxicity and potential neuroprotective effect against neurotoxin 6-hydroxydopamine (6-OHDA). The results show that ligands 2 and 5 possessed neither significant antiproliferative effects, nor necrotic and mitochondrial toxicity (up to concentration of 50μM). Moreover, ligand 2 showed weak neuroprotective effect at the 50μM against 100μM toxic dose of 6-OHDA. Our results indicate that modulatory effects of ligands 2 and 5 on human α1-GLYRs as well as on STR-induced convulsion can provide further insights for the design of therapeutic agents in treatment of epilepsy and other pathological conditions requiring enhanced activity of inhibitory glycine receptors.
Keywords: Anticonvulsant; Human α1-glucine receptor; Inhibitor; Phenyl alanine derivatives; Potentiator; Strychnine.
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